{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMOCS3 encodes a dual‐domain protein that plays a central role in the biosynthesis of the molybdenum cofactor (Moco) and in cytosolic tRNA thiolation. Its N‐terminal domain, which is homologous to the Escherichia coli MoeB protein, mediates the adenylation of target proteins such as MOCS2A and URM1. In parallel, the C‐terminal rhodanese‐like domain (RLD) catalyzes the generation of a persulfide on a conserved cysteine (notably C412) that is essential for the thiocarboxylation reaction. These two enzymatic functions ensure that sulfur is appropriately transferred for the formation of the dithiolene group of molybdopterin and for the 2‐thiolation of wobble uridine in specific tRNAs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistic studies have revealed that MOCS3 receives its sulfur via a persulfide intermediate generated by the interaction with an L‐cysteine desulfurase (NFS1), rather than directly utilizing thiosulfate as the physiological sulfur source. Similarities between human MOCS3 and its yeast homologue Uba4 have been documented, with both proteins engaging in the adenylation of substrates and catalyzing sulfur transfer reactions. Detailed mutagenesis and biochemical analyses have further underscored the critical importance of the active‐site configuration in the RLD for efficient sulfur relay, while structural studies have begun to unveil how the N‐ and C‐terminal domains communicate during the catalytic cycle."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, defects in MOCS3 have been linked to impaired Moco biosynthesis, as evidenced by the markedly reduced sulfite oxidase activity and loss of tRNA thiolation observed in cellular knockout models and in patients carrying missense mutations in the ubiquitin‐like domain. These observations highlight the dual role of MOCS3 in crucial sulfur transfer pathways, bridging metabolic cofactor biosynthesis and tRNA modification, and underscore its significance in human disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andreas Matthies, K V Rajagopalan, Ralf R Mendel, et al. 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Major differences in substrate specificity between eukaryotic and bacterial homologs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1742-4658.2007.05811.x"}], "href": "https://doi.org/10.1111/j.1742-4658.2007.05811.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17459099"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17459099"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jennifer Schmitz, Mita Mullick Chowdhury, Petra Hänzelmann, et al. 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